PROJECT SUMMARY This proposal explores the cellular and molecular mechanisms of non-tissue damaging near-infrared (NIR) laser to augment epicutaneous immunotherapy (EPIT) with the ultimate purpose of developing an effective, painless, side effect-free treatment for food allergy. Food allergy affects approximately 5% of adults and 8% of children and is steadily growing in Western countries lately, posing medical and economic burden on our society. Despite our improved understanding of food allergy in recent years, the causal treatment for this condition is yet to be developed. EPIT involves non-invasive administration of relatively small dose of causative allergen via skin using simple technique and has the numbers of advantages over other candidate therapies. The efficacy and durability of EPIT, however, has been modest in desensitizing patients with mild but applicable adverse events in clinical trials. Chemical and biological agents, which have been used to increase the efficacy of vaccines against infectious diseases, have been shown to improve the efficacy of immunotherapy and could be used to overcome the shortcomings. However, these agents are designed to trigger a ?danger signal? in the immune system to enhance the immune response and linked to unexpected side effects. The novel methodology to improve the efficacy and durability of EPIT would constitute a significant advance to achieve clinical significance. We have previously shown that a brief exposure of skin to non-tissue damaging NIR laser augments the immune response to the intradermal vaccine via enhancing migration of skin-resident migratory dendritic cells (migDCs) into lymph nodes without overt inflammation or side effect. These provocative findings led us to hypothesize that a combination approach of the NIR laser and EPIT using the non-invasive hydrogel patch system offers an optimal microenvironment for migDCs to migrate into the secondary lymphoid tissue and efficiently mount the subsequent immune response, thus inducing the robust and durable tolerance response to food allergen. The specific aims of this proposal are: (i) Determine whether the NIR laser in combination with hydrogel patch-based EPIT enhances gut-homing regulatory T cells (Tregs) and reduces clinical symptoms in a model of clinically relevant peanut allergy, and (ii) Determine the role of the distinct migDC subset in induction of Treg populations mediating suppression of allergic TH2 responses by the NIR laser in the context of EPIT. Unlike the conventional chemical or biological agents, laser is a physical parameter inducing selective signaling to enhance activation of migDCs, and therefore does not pose any safety or stability issues. Laser does not require special formulation when being combined with immunotherapeutic either. In view of the fact that NIR lasers have been used in the field of medicine for decades, and the hydrogel patch system has been proved to be safe and effective in clinical testing, successful project completion will allow for rapid translation into human studies of this combination approach, which is expected to gain fast approval by regulatory authorities. The development of such a needle- free, safe, effective treatment for food allergy would have an immediate impact in the clinic.